VEGF and Angiopoietin-1 exert opposing effects on cell junctions by regulating the Rho GEF Syx
VEGF and Angiopoietin-1 exert opposing effects on cell junctions by regulating the Rho GEF Syx
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DOI：
10.1083/jcb.201207009
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发表时间：
2012-12-24
影响因子：
7.8
通讯作者：
Anastasiadis, Panos Z.
中科院分区：
文献类型：
--
作者：
Ngok, Siu P.;Geyer, Rory;Anastasiadis, Panos Z.
血管内皮生长因子（VEGF）和Ang 1（Angiopoietin-1）对血管通透性具有相反的作用，但这些作用的分子基础尚不完全清楚。在本文中，我们报告，血管内皮生长因子和血管生成素1调节内皮细胞（EC）的连接，通过确定本地化的RhoA特异性鸟嘌呤核苷酸交换因子Syx。Syx被Crumbs极性复合体的成员招募到连接处，并通过激活透明蛋白促进连接完整性。VEGF导致Syx从细胞连接处易位，促进连接处解体，而Ang 1维持Syx在连接处，诱导连接稳定。VEGF诱导的Syx从EC连接处的易位是由PKD 1（蛋白激酶D1）介导的Syx在Ser（806）的磷酸化引起的，这减少了Syx与其连接锚的结合。为了支持Syx在调节EC连接中的关键作用，syx（-/-）小鼠具有缺陷性连接，导致血管渗漏、水肿和心脏功能受损。
Vascular endothelial growth factor (VEGF) and Ang1 (Angiopoietin-1) have opposing effects on vascular permeability, but the molecular basis of these effects is not fully known. We report in this paper that VEGF and Ang1 regulate endothelial cell (EC) junctions by determining the localization of the RhoA-specific guanine nucleotide exchange factor Syx. Syx was recruited to junctions by members of the Crumbs polarity complex and promoted junction integrity by activating Diaphanous. VEGF caused translocation of Syx from cell junctions, promoting junction disassembly, whereas Ang1 maintained Syx at the junctions, inducing junction stabilization. The VEGF-induced translocation of Syx from EC junctions was caused by PKD1 (protein kinase D1)-mediated phosphorylation of Syx at Ser(806), which reduced Syx association to its junctional anchors. In support of the pivotal role of Syx in regulating EC junctions, syx(-/-) mice had defective junctions, resulting in vascular leakiness, edema, and impaired heart function.